Certain pyridyl cyclopropylamides

ABSTRACT

COMPOUNDS HAVING THE FORMULA:   (R)N,(CYCLOPROPYL-NH-CO-)-PYRIDINE   WHREIN R IS A MEMBER SELECTED FROM THE GROUP CONSISTING OF HYDROGEN, HALOGEN, HYDROXYL ACYL GROUPS OF 1 TO 4 CARBON ATOMS, CARBOXYLIC ACID GROUPS, CARBOXYLIC ACID ESTER GROUPS, AMIDO GROUPS, SULFONIC ACID GROUPS, SUL, FONAMIDO GROUPS AND HYDROCARBON GROUPS OF 1 TO 8 CARBON ATOMS AND N IS O, 1 OR 2. THE UNSUBSTITUTED DERIVATIVES ARE USEFUL IN THE TREATMENT OF ARTERIAL HYPERRTENSION, AND THE SUBSTITUTED DERIVATIVES ARE PARTICULARLY USEFUL AS DIURETICS, HYPOTENSIVE, AGENTS, SEDATIVE AND AS ANORECTIC AGENTS.

United States Patent Oflice 3,822,277 Patented July 2, 1974,

US. Cl 260-295 AM 11 Claims ABSTRACTOF THE DISCLOSURE Compounds havingthe formula:

cm CO-NHCH wherein -R is a member selected from the group consisting ofhydrogen, halogen, hydroxyl acyl groups of 1 to 4 carbon atoms,carboxylic acid groups, carboxylic acid ester groups, amido groups,sulfonic acid groups, sulfonamido groups and hydrocarbon groups of l to8 carbon atoms and n is O, 1 or 2. The unsubstituted derivatives areuseful in the treatment of arterial hypertension, and the substitutedderivatives are particularly useful as diuretics, hypotensive agents,sedatives and as anorectic agents.

This is a continuation of application Ser. No. 807,395, filed Mar. 14,1969, now abandoned.

This invention relates to various novel compounds having an amidefunction and their use in therapy. More particularly, it relates to thepreparation and use of cycle propylamides derived from pyridinecarboxylic acids. Additionally, the invention relates to the preparationand use of derivatives of these compounds that are substituted in thearomatic ring with various moieties, such as halogen, acyl, carboxyl,ester, amido, sulfonic, sulfonamido or hydrocarbon groups.

The cyclopropylamides of the invention by the formula:

are represented These compounds, which have the form of whitecrystalline powders, are soluble in water and exceedingly stable. Theyare derived from the reaction between a pyridine carboxylic acid (oracyl halide or alkyl ester thereof) and acyclopropylamine. Thesecompounds are prepared either (a) by the direct elimination of a watermolecule between the pyridine carboxylic acid and the cyclopropylamine,if desired in a solvent and in the presence of a suitable catalyst, or(b) by the action of a pyridine carboxylic acid halide on thecyclopropylamine,

if desired inthe presence of an alkaline agent which binds the hydracidformed during the course of the reaction. Alternative to the latterreaction, the cyclopropylamine may be reacted with a low molecularweight alcohol ester of the pyridine carboxylic acidif desired in asuitable solvent.

A specific example of a useful compound belonging to the above-describedgroup is the cyclopropylamide of 2- pyridine carboxylic acid, i.e.,picolinic cyclopropylamide. This compound is a liquid and is capable ofproducing well crystallized salts with organic or mineral acids. I

be amidated) or (5) at least one hydrocarbon group Thesecompounds, aswell as the salts thereof with organic or mineral acids, are soluble inwater and yield aqueous solutions having a pH close to neutral (around7). They are stable and can be formulated in all of the customarypharmaceutical forms, if desired in association with other activeprinciples, and in the presence of any compatible excipients.

Among the compounds of the present invention, nicotinic:cyclopropylamide and isonicotinic cyclopropylamide have a particularlylow toxicity. As a matter of fact, the LD of these compounds is of theorder of 1.250 mg./kg. as measured intraperitoneally in mice. Incontrast thereto, picolinic cyclopropylamide has a toxicity which isalmost three times higher, measured under the same conditions.

The compounds described hereinabove, particularly the picolinic,nicotinic and isonicotinic cyclopropylamides as well as the saltsthereof with mineral or organic acids, show a particularly interestingactivity with respect to the functioning of the nervous system. Theyexert a longlasting hypotensive action, free from secondary effects, andthus are particularly useful for the treatment of arterial hypertension.

The record of the arterial tension or pressure of a dog treated withvarying quantities of isonicotinic cyclo-' propylamide, for example,shows a tension drop which passes from 12 cm. to 6 cm. of mercury fordoses close to 50 mg./kg., the latter value being maintained for morethan minutes. During this experiment, no secondary action whatsoever wasobserved on either the respiration or on the intestinal motility.However, it is to be recognized that there is a strong reduction of thediuresis while the animal is put in hypotension.

Accordingly, compounds of the character described hereinabove permit aparticularly effective treatment of hypertension without secondaryeffects or intolerances. Two examples of pharmaceutical preparationscontaining these compounds are given below for purposes of illustration.However, the details thereof should considered as limitative of theinvention.

EXAMPLE 1 EXAMPLE 2 Preparation of suppositories. Suppositories areprepared containing 200 mg. of nicotinic cyclopropylamide and sufficientexcipient (QS) to give finished suppositories of 3 grams each. Theposology to be employed therewith is 1 to 4 suppositories per day (200mg. to 800 mg. per day of active principle).

In another embodiment of the invention, it has been found that compoundshaving the formula wherein R is (1) at least one substituent selectedfrom the group consisting of hydrogen and halogen radicals (halogenreferring to chlorine, bromine, iodine or fiuorine atoms) (2) at leastone hydroxyl group (which can be acylated with a carboxylic acid having1 to 4 carbon atoms), (3) at least one carboxylic acid group (which canbe esterified or amidated), (4) at least one sulfonic acid group (whichcan not be having from 1 to 8 carbon atoms, which can be either branchedor straight-chain alkyl or cyclic, have particularly interestingproperties which permit their use in various applications. The lattersubstituent (hydrocarbon groups) may contain one or several multiple(double or triple) bonds. The described R substituent as well as thecarboxylic cyclopropylamide group may occupy any of the positionson thepyridine ring. Also usefulare the saltsof these compounds with mineralor organic acids, as well as the addition derivatives thereof throughthe nitrogen of the pyridine nucleus, such as the halo- "alco'holates,the sulfo-alcoholates and the amine oxides. Compounds containingsubstitution groups in the pyridine nucleus are prepared as describedabove with respect to the unsubstituted compounds, i.e., fromsubstituted pyridine carboxylic acids having the formula:

wherein R has the same meaning as described hereinabove. Reactiontakesplace either by the direct elimina-. tion of a water molecule betweenthe substituted pyridine carboxylic acid and the cyclopropylamine(operating, if desired, in an inert solvent and in the presence of asuitable catalyst) orby the action of a substituted carboxylic pyridineacid halide-or a low molecular weight alkanol ester of the substitutedpyridine carboxylic acid on the cyclopropylamine (if desired, in aninert solvent and, in the case of the acid halide, in the presence of analkaline agent which fixes or binds the hydracid formed during thecourse of the reaction). These compounds may also be obtained in goodyield either by the direct introduction of the R substituent into thepyridine ring of a cyclopropylamide having the formula or by thesubstitution of the R group for; an .R' group which has previously beenintroduced into the nucleus. For example, if it is desired to obtaincompounds having chlorine atoms in the pyridine nucleus, it is easy toobtain them by reacting the corresponding hydroxylated derivatives withan appropriate chlorination agent.

.The nuclear-substituted compounds are white crystalline powders and arecompletely stable. They are generally sufficiently soluble in water butmay be trans formed into very soluble salts by acidification of thenitro-- gen atom of the pyridine nucleus with an appropriate acid. Thesecompounds have the property of being extremely active moleculeswith-respect to the functioningof the nervous system. They generallyhave a low toxicity and can be used in various pharmaceutical andveterinary applications. c -In another embodiment of the presentinvention, the present inventor has found that compounds having thefollowing formula:

v 4 ficient, they may be easily converted. into salts withmineral ororganic acids, the latter likewise falling within the framework of thepresent invention. Other useful derivatives thereof include the additionderivatives through the nitrogen atom of the pyridine nucleus, such asthe halo-alcoholates, the sulfo-alcoholates and the amine oxides. v Y

These derivatives arealso obtained in accordance with the'reactionsdescribed above from substituted carboxylic' pyridine acids having theformula coon,

wherein R has the same meaning as described hereinabove. The reaction iscarried out either by the direct elimination of a water molecule betweenthe carboxylic pyridine acid and cyclopropylamine (if desired, in thepresence of a solvent and a suitable catalyst) or by reaction betweenthe cyclopropylamine and a carboxylic pyridine acid halide (if desired,in'the presence of an alkaline agent designed to fix the hydracid formedduring with the derivatives described above, -if it is desired toobtaincompounds having chlorine substituents in the nucleus, these can bereadily obtained by reacting thecorresponding hydroxylated derivativeswith an appropriate chlorination agent. Y

Exemplary of compounds falling within the described categories arethefollowing: Y

picolinic cyclopropyl amidenicotinic cyclopropyl amide isonicotiniccyclopropyl amide 5-chloro-cyclopropyl nicotinamide5,6-dichloro-cyclopropyl nicotinamide 2-chloro-cyc1opropyl nicotinamide2,6-dihydroxycyclopropyl isonicotinamide. 2,6-dichloro-cyclopropylisonicotinamide Y 2,6-dichloro-cyclopropyl nicotinamide2-bromo-cyclopropyl nicotinamide 2,4-dibromo-cyclopropyl nicotinamideo-bromo-cyclopropyl nicotinamide2-bromo-6-chloro-cyclopropylnicotinamide 2-fluoro-cyclopropylnicotinamide 2,6-difluoro-cyclopropyl nicotinamide Z-methyl-cyclopropylnicotinamide 2-ethyl-cyclopropyl nicotinamide 2-phenyl-cyclopropylnicotinamide 2-phenyl-6-chloro-cyclopropyl nicotinamide2-phenyl-6-bromoecyclopropyl nicotinamide Z-phenyl-S-chloro-cyclopropylnicotinamide Z-phenyl-S-bromo-cyclopropyl nicotinamide2-(Z-chlorophenyl)-cyclopropyl nicotinamide2-(4-chlorophenyl)-cyclopropyl nicotinamide I 2- (4-methoxyphenyl-cyclopropyl nicotinamide 4-phenyl-cyclopropyl nicotinamide2-anilino-cyclopropyl nicotinamide as well as the isomer4-hydroxy-cyclopropyl nicotinamide 4,5-dihydroxy-cyclopropylnicotinamide and the hydroxysubstituted derivatives thereof .withmethyl, ethyl, propyl, isopropyl, and butyl groups zramino-cyclopro ylni otinamide 2amino-cyclopropyl isonicotinamide. 4 sulfamido-cyclopropylnicotinamide The compounds according to thetinvention, which haveperfect-stability, may be formulated in any of the customarypharmaceutical forms, such as inert tablets, sugarcoated tablets,solutions which are drinkable, injectable preparations, granulated.products and-syrups, if desired, in -;.combination with other activeprinciples and in the presence of any compatible excipients.

All of the compoundsof the" invention have theadvantage ofa generallylow toxicity, even with repeated administrations, and display in varyingdegrees diuretic, hypotensive and sedative properties which make itpossible to use these products in a plurality of applications, all themore so since their action is generally not accompaniedby disturbingsecondary eflects. The nuclear-sub stituted derivatives of the inventioneffect a potentialization of sleep, such as that caused by hypnoticagents. Measured in mice, this is apparent from a reduction of the timerequiredforthe onset of sleep and from an increase in the duration ofthe sleep, varying from 25 to 75% thereof, depending upon the cases. Thesubstituted derivatives of the invention show a diuretic action which ismanifested particularly in the molecules-containing one or severalhalogen atoms and most especially with compounds containing chlorine inthe nucleus.

The measurements concerningsthe increase of the diuresis, which werecarried out on male rats, have made. it possible to find anincreaseproportional to the dosage and which varies from 50 to 400% as afunction thereof. It is particularly interesting to note that thisincrease of the diuresisdoes not entail animportant variation of thecliminationratesof sodium and potassium. As noted above, the substitutedderivatives of the invention have equally more or less markedhypotensive properties which are not accompanied by secondary effects,particularly on the cardiac and respiratory systems.

Finally, it has also been found that the last-described derivatives aremoderators for the consumption of foodstu1fs,. i. e., appetitecurbingagents. The anorectic elfect becomes evident at doses varying from 5 .to50 mg./kg.- in rats and may involve a reductioniof food consumption orintake of from 20 to 30%.,This effect is particularly clear duringrepeated administrationsfor severaLdays in arow. i

All of these properties taken together make itpossible toprepare,vWiththe aid of the compounds of the present invention, medicines whichare particularly effective and; well tolerated, especially from thecardiac point of view, for treating disorders of: the generalmetabolism, conditions of obesity and hypertension. Moreover, the verylow toxicity of the compoundsaccording to the present inventionconstitutes a considerable advance as. compared to the related compoundsknown to date, particularly those having an amphetaminic structure. I v

The following examples-illustrate pharmaceutical prep arations inaccordance with the inventionand are not to be considered as limiting incharacter.

exaihi fi y f Tablets are prepared from 2 50 mgt of cyclo propylamideandsufficient excipienti (Q3) for finished tablets of 350 nigeach. V p II EXAMPLE4' Sugar-coated tablets are prepared jet 2,6-dichlorocyclopropyl nicotinamide and ,sufiicient exmg. each.

cipient (QS) togive finished sugar-coated tablets .of 2 5 1 EXAMPLE as aSuppositories are prepared' 'fr'om' 200 mgfof 2,6-dihydroxy-cyclopropyl4 f carboxy pyridine and sufficient of methyl isonicotinamide, 23 gramsof cyclopropylamine excipient (QS) for finished suppositories of 25grams each.

The posology to be employed with the nuclear-substituted derivativesvaries from 100 to 500 mg. per day, or more if desired. The very lowtoxicity thereof makes it possible to repeatedly administer them withoutany intolerance or habit-forming phenomena.

Accordingly, one of the objects of the present invention is to providenovel compounds having an amide function.

Another object of the present invention is to provide a process for thepreparation of the described compounds which may 'be carried out in anefiicacious and relatively simple manner.

A further object of the invention is to provide pharmaceuticalpreparations containing the described novel compounds.

A still further object of the invention is to provide organic compoundswhich are useful in therapy.

These'and other objects and advantages of the present invention shouldbecome apparent to those skilled in the art from a consideration of theabove description as well as the following examples.

The following examples concerning the preparation of the compounds ofthe present invention are given merely as illustrative and are not to beconsidered as limiting. It is to be understood that the conditions ofreaction ma be varied from the specific details given.

EXAMPLE 6 Preparation of cyclopropyl nicotinamide. Nicotinic acidhydrochloride (1 mole) is prepared by reacting excess thionyl chloridewith nicotinic acid. After concentration of the excess of thionylchloride, the residue is recovered by means of benzene and, whilecooling is effected in such a manner that the temperature will notexceed +5, cyclopropylamine diluted with benzene is added while stirringuntil a distinctly alkaline reaction is achieved;(about 2.5 moles).Stirring is continued for 2 hours at ambient temperature and thecrystallized cyclopropylamine hydrochloride is then centrifuged.Thereafter, the solution is concentrated in vacuo and the residuerecovered with an equal quantity of benzene. A white crystallizedproduct is separated which is centrifuged and recrystallized in a volumeof benzene.

'Thecyclopropyl nicotinamide is thus obtained in a yield of to in theform of a white crystalline powder which is soluble in water andalcohol, insoluble in ether and which melts at 84-85 C. (microscope).This product, when subjected to elementary analysis, gives the followingresults:

C, 66.7, 66.6; H, 6.31, 6.31; N, 17.16, 17.19. Calculated for C H NO=l62.19. C, 66.6; H, 6.17; N, 17.28.

The nearly perfect coincidence between the figures obtained and thetheoretical figures confirms the exactness of the formula proposed forthe new compound.

EXAMPLE 7 Preparation of cyclopropyl isonicotinamide. 50 grams and cc.of glycol are placed into a round-bottomed fiaskand the mixture isallowed to stand at 50 C. At the end'of several hours, a crystallizedproduct begins to separate. When the reaction is terminated, which maytake severaldays, the reaction mixture is cooled, frozen, centrifuged,washed in acetone and then dried at 50 C., thereby yielding 25 grams ofa crystallized product. By concentration of the mother liquors andrecovery in acetone, a second batch of 17 grams is obtained. The twobatches are combined and dissolved in 3 volumes of hot acetone. Afterfiltration, crystallization and drying, 35 to 37 grams of a whitecrystallized product is obtained, the product having a melting point of-116 C. (microscope) and being soluble in waterand alcohol.

7 When subjected to the elementary gives the following figures:

C, 66.42, 66.59; H, 6.55, 6.34; N, 17.4, 17.26. Calculated for C H NO=162.19. C 66.65; H, 6.17; N, 17.28. The coincidence of the figuresfound with the theoretical values establishes with certainty thestructure of the new compound.

EXAMPLE 8 Preparation of picolinic cyclopropylamide; 255 grams of theethyl ester of alpha-picolinic" acid .is dissolved in .50 ml. of glycolin a reaction apparatus equipped with a stirring device or mechanism;Added thereto is 12 grams of cyclopropylamine. The mixture is stirred at50 C. for 15 hours. Thereafter, themixture is concentrated in vacuo andthen the residue is distilled un-. der a high vacuum. The principalfraction passing. at 95- 96 C. under 0.4 mm. of mercury is collected. Itis a colorless :liquid which after, redistillation, has a refractionindex n of 1.5605. The chromatography thereof in the gaseous phasereveals only a single peak and the elementary analyses are insubstantially perfect agreement with the theoretical values calculatedfor C H N O.

Theproduct thus obtained may also be easily titrated in perchloric acid.It is soluble in cold Water at the rate of about 14% and is equallysoluble in alcohoL-ether and acetone. It yields salts with the mineralor organic acids. For example, the hydrochloride thereof is a whitecrystalline powder which is very soluble in water and which crystallizeseasily in methyl ethyl ketone. It melts at 132134 C. (microscope) and,in the aqueous solution, has a pH of between 1.5 and 2.

EXAMPLE 9 Preparation of 5 chloro-cyclopropyl nicotinamide. 65 grams of5-chloro-methyl nicotinate (melting point 88-90 C.) is dissolved in 80ml. of ethylene glycol and 24 grams of cyclopropylamine is addedthereto. Themixture is allowed to stand at 50 C. for severalhours'.When] the reaction is terminated, the glycol is concentrated invacuo andthe residue is recovered with acetonefyielding crystalline5-chloro-cyclopropyl nicotinamide. The residue may be centrifuged,washed and dried and the product may be recrystallized in isopropylalcohol, if desired. f

Obtained in this manner is 40 to 45'grar'ns of S-chlorocyclopropylnicotinamide which, when subjected to ele mentary analysis, gives thefollowing figures:

C, 55.1, 55.2; R, 4.60, 4.63; N, 14.1, 14.15; Cl, 17.7. Calculated for CH N 0Cl=196.70. C, 54.90; R, 4.57; N,

analysis, this The agreement between the theoretical values and thefigures found establishes the structure of the new compound withcertainty.

EXAMPLE 10 Preparation of 5,6-dichloro-cyclopropyl nicotinamide:

on, C1 ooNHol 0 Hz The reaction is conducted in a manner analogous thatdescribed in Example 9, except that steam rs. methyl nicotinate (m.p. 68C.) is employed asareactant. As a result, 5,6-dichlorocyclopropylnicotinamide is ob; tained in the form of white needles which arenotyery soluble in water in a yield of 65%.

EXAMPLE 11 Preparation of 2-chloro-cyclopropyl nicotinamide" Thehydrochloride of 2-chloro-nicotinic acid is prepared by reacting onemole thereof (melting, point 193 C.) with an excess of thionyl chloride.When the reaction is com lete, the excess is eliminated, the residue isre- -s covered with benzene and, while cooling insu'ch men; ner that thetemperature does not exceed +5 C.. cy clopropylamine is added'whilestirring 'until a distinctlyalkaline'reaction is' obtained (about 2.5moles). H

'Stirring "is continued in the cold for'2 hours and the mixtureis'brought to reflux for 3 2 hour. The mixture is cooled and theresultant crystallized cyclopropylaminehy'- drochloride is centrifuged.The solution is washed idafv concentrated watenactone' mixture. The2-chloro-cyc1o I'Ih'ev yield reaches '85 to'90%. The product meltsat IC.jand givesanalytical results in. substantially perfecti oonformitywiththe theoretical values.

- g EXAMPLE 12 r Preparation of 2,6-dihydroxy cyclopropylisonicotinariiide; C9H10O3N2 a v I V A mixture of 21.5 grams of 2,6-dihydroxy-methyl nicotinate, 125 ml. of ethylene glycol'and 30 grams oflcyclopropylamine is kept in the ovenat 50". C. fol .150 hours.Everything passes progressively into solution. When the reaction isterminated, the mixture is concentrated in'vacuo and the residue isrecovered with m1, of, alcohol. The crystallized product is frozen andcentrifuged; washed in alcohol and then in water. Obtained in ,thismanner are 20 grams of crude product which, when recrystallized inacidic water, gives the desired productin good yield in the form of paleyellow needles which are soluble in hot water and which melt withdecomposition at 234-236? C. (microscope). I The product is subjected tothe elementary analysis and gives the following results: p I C, 55.44,55.21; H, 5.33; .5.30; N, 14.43.114.49. Cal culated for C H O3N =194.19.C, 55.66; H, 5.19; N, 14.43. ,EXAMPLE 13 I '.[2,G-dichlorocyclopropylisoniootinamide 2 5 When the product obtained according to Example 112'is treated with a halogenation agent, for example, with" phosphorusoxychloride or pentachloride', in the' presence ofan-inert solvent, 2,6-dichloro-cyclopropyl isonicotin amide is obtained withoutdifficulty.'The'brominated' de rivative may be obtained in acorrespondingway. The

yield reaches to' Qffthe theoretical.

By operating 'in an analogous manner, the following oducts forexample,have also been prepared fi bromo-cyclopropyl nicotinamide2-bromo-6-'chloro-cyclopropyl nicotinamide 2-fluoro-cyclopropylnicotinamide 2,6-difluoro-cyclopropyl' nicotinamide2-methyl-cy'clopropyl nicotinamide 2-ethyl-cyclopropyl nicotinamide2-phenyl-cyclopropyl nicotinamide 2-phenyl-6-chloro-cyclopropylnicotinamide 2-phenyl-6-bromo cyclopropyl nicotinamide2-phenyl-5-chloro-cyclopropyl nicotinamide 2-phenyl-5-bromo-cyclopropylnicotinamide laminae-cyclopropyl. nicotinamide, s Lea 13s: t. A}, s;

, the bI'OlIIOrCYClOPIOpYl picolylamides 4-hydroxy-cyclopropylnicotinamide 4,5-dihydroxy-cyclopropyl nicotinamide (and the derivativesthereof substituted through the hydroxyl groups by methyl, ethyl,propyl, isopropyl and butyl groups) 2-amino-cyclopropyl nicotinamideZ-amino-cyclopropyl isonicotinamide 4-sulfamido-cyclopropylnicotinamide.

The invention being thus described, it will be obvious that the same maybe varied in many ways. Such variations are not to be regarded as adeparture from the spirit and scope of the invention, and all suchmodifications as would be obvious to one skilled in the art are intendedto be included herein.

'I claim:

1. A compound having the formula:

wherein R is a member selected from the group consisting of hydrogen,hydroxyl, halogen selected from the group consisting of bromo, chloro,iodo, and fluoro, acyl groups of 1 to 4 carbon atoms, and hydrocarbongroups of 1 to 8 carbon atoms which are linear or lateral branched alkylor cyclic groups, and n is 0, 1 or 2, with R being a halogen group onlywhen n is 1 or when n is 2, and one of the R groups is other thanhalogen, or both R groups are halogen and are in the 2-, 4-positions,the 2-, S-positions, or the 5-, 6-positions.

2. Cyclopropyl nicotinamide.

3. Cyclopropyl isonicotinamide.

4. Picolinic cyclopropylamide.

5. S-Chloro-cyclopropyl nicotinamide.

6. 5,6-Dichloro-cyclopropy1 nicotinamide.

7. Z-Chloro-cyclopropyl nicotinamide.

8. A compound according to claim 1, wherein R represents hydroxylgroups.

9. A compound according to claim 1, wherein R represents halogen groups.

10. A compound according to claim 1, wherein R represents hydrocarbongroups selected from the group consisting of methyl, ethyl, propyl,isopropyl, butyl and phenyl.

11. A compound according to claim 1, wherein R represents acyl groups of1 to 4 carbon atoms.

References Cited UNITED STATES PATENTS 9/1968 Horrom 260-2949 6/1956Ginell et a1. 260--295 AM OTHER REFERENCES ALAN L. ROTMAN, PrimaryExaminer US. Cl. X.R.

